Pro-Oncogenic Role of a Mitochondrial Lipid Kinase in CLL
线粒体脂质激酶在 CLL 中的促癌作用
基本信息
- 批准号:10651077
- 负责人:
- 金额:$ 16.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-10 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdultAgammaglobulinaemia tyrosine kinaseAntigensApplications GrantsAutomobile DrivingB lymphoid malignancyB-Cell ActivationB-Cell Antigen ReceptorB-LymphocytesBCL2 geneBehaviorBindingBiologicalBiological ProcessBloodBone MarrowCell ProliferationCell SurvivalCellsCellular biologyCervical Squamous Cell CarcinomaChronic Lymphocytic LeukemiaClinicalCytoplasmDataDedicationsDiagnosisDiglyceridesDiseaseDisease ProgressionEarly treatmentEpigenetic ProcessEsophageal Squamous Cell CarcinomaEventFRAP1 geneGeneticGenetic TranscriptionGoalsHeterogeneityHumanIn VitroIndolentInduction of ApoptosisInvestigationJAK2 geneLYN geneLipidsLiposomesMalignant - descriptorMalignant neoplasm of prostateMediatingMediatorMitochondriaMolecularMonoglyceridesNuclearOncogenesOncogenicOralOrganPI3K/AKTPIK3CG genePTEN genePathogenesisPathway interactionsPatient-Focused OutcomesPatientsPhosphatidic AcidPhosphotransferasesProcessProductionProliferatingProto-Oncogene Proteins c-aktPublic HealthReceptor InhibitionReceptor SignalingRegulationResistanceRichter&aposs SyndromeRisk FactorsRoleSTAT3 geneSignal TransductionSignaling MoleculeSmall Interfering RNASpleenSquamous cell carcinomaTestingTherapeuticTimeTransgenic MiceTreatment outcomeTumor BurdenUp-Regulationcell growthcell typechronic lymphocytic leukemia cellclinical heterogeneitycohortcytotoxichigh riskimprovedin vivoinhibitorinhibitor therapyinnovationinsightkinase inhibitorlarge cell Diffuse non-Hodgkin&aposs lymphomaleukemialymph nodeslysophosphatidic acidmalignant breast neoplasmmitochondrial membranemouse modelnoveloverexpressionprognosticrelapse patientssurvival outcometargeted agenttargeted treatmenttherapeutic targettherapy outcometherapy resistanttumortumorigenesis
项目摘要
PROJECT SUMMARY
Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia
diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these
are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding
the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation.
CLL is a disease characterized by extensive clonal proliferation and accumulation of malignant B lymphocytes
in the blood, bone marrow, spleen, and lymph nodes. CLL shows remarkable clinical heterogeneity, with some
patients pursuing an indolent course, while others progress rapidly and require early treatment. In the past 10
years, new insights into the biological function of a mitochondrial lipid kinase, acylglycerol kinase (AGK), as a
key oncogene that is highly expressed in a range of tumor types, including prostate cancer, breast cancer,
cervical squamous cell carcinoma, and esophageal squamous cell carcinoma have been established. Most
recently, we found aberrantly high level expression of AGK in CLL cells from ~60% of pre-therapy CLL patients.
However, the mechanism of aberrant upregulation of AGK in CLL cells, and its precise functional contributions
to CLL cell biology and pathogenesis remain unknown. Interestingly, we detected nuclear/cytoplasmic
localization of AGK in some CLL clones suggesting its multi-functional role. In line with this, we found that siRNA-
mediated depletion of AGK in primary CLL cells resulted in marked inhibition of constitutively active multiple
signal mediators including AKT, Erk1/2, LYN, BTK (downstream targets of BCR signal) and JAK2. Our
preliminary findings also indicate that MYC may regulate AGK expression in CLL cells. Our combined data
suggest that aberrant expression of AGK may potentiate cell survival signals including BCR and JAK2 in some
CLL clones resulting in resistance to BCR-targeted therapies. Therefore, the central hypothesis of this application
is that aberrant expression of AGK in some CLL clones represents highly aggressive CLL with shorter time to
therapy. We also postulate that AGK upregulation potentiates CLL cell survival signals and resistance to BCR-
targeted agents. We propose – Aim 1: Evaluate if aberrant expression of AGK in CLL cells drives disease
progression; Aim 2: Define the mechanism of AGK upregulation and its role in CLL cell biology, signaling and
potential as a therapeutic target. The proposed in-depth studies will assess if “high AGK” level in CLL cells serves
as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of AGK aberrant
expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies
have enormous potential to establish a new prognostic parameter and therapeutic avenue via targeting AGK in
CLL cells with or without the current BCR-targeted therapy, ibrutinib.
项目摘要
慢性淋巴细胞白血病是一种成人B细胞恶性肿瘤,约占白血病的三分之一
在美国的诊断虽然B细胞受体(BCR)信号抑制剂正在改变CLL的管理,但这些药物可能会影响CLL的治疗。
不能治愈,并且会产生抗药性;通常会导致更具侵略性的疾病。鉴于此,理解
驱动CLL肿瘤发生和治疗抗性的分子事件值得深入研究。
CLL是一种以恶性B淋巴细胞广泛克隆性增殖和聚集为特征的疾病
在血液骨髓脾脏和淋巴结里CLL显示出显著的临床异质性,其中一些
病人追求无痛过程,而其他人进展迅速,需要早期治疗。过去10
近年来,对线粒体脂质激酶--酰基甘油激酶(AGK)的生物学功能有了新的认识,
在一系列肿瘤类型中高度表达的关键癌基因,包括前列腺癌,乳腺癌,
宫颈鳞状细胞癌和食管鳞状细胞癌已经确立。最
最近,我们在约60%的治疗前CLL患者的CLL细胞中发现异常高水平的AGK表达。
然而,CLL细胞中AGK异常上调的机制及其确切的功能贡献
CLL的细胞生物学和发病机制仍然未知。有趣的是,我们检测到细胞核/细胞质
AGK在一些CLL克隆中的定位表明其多功能作用。与此一致,我们发现siRNA-
在原代CLL细胞中介导的AGK消耗导致组成性活性多个细胞因子的显著抑制,
信号传导介质包括AKT、Erk 1/2、林恩、BTK(BCR信号传导下游靶点)和JAK 2。我们
初步发现也表明MYC可能调节CLL细胞中AGK的表达。我们的综合数据
提示AGK异常表达可能在某些情况下增强细胞存活信号,包括BCR和JAK 2,
CLL克隆导致对BCR靶向疗法的抗性。因此,本申请的中心假设
某些CLL克隆中AGK的异常表达代表高度侵袭性CLL,
疗法我们还假设AGK上调增强CLL细胞存活信号和对BCR-1的抗性。
目标代理人目的1:评估CLL细胞中AGK的异常表达是否驱动疾病
目的2:确定AGK上调的机制及其在CLL细胞生物学、信号传导和免疫调节中的作用。
作为治疗靶点的潜力。拟议的深入研究将评估CLL细胞中的“高AGK”水平是否有助于
作为CLL进展、至治疗时间和治疗结局的风险因素;定义AGK异常的影响
表达对CLL细胞存活和对当前BCR靶向疗法的抗性的影响。因此,拟议的研究
通过靶向AGK,具有建立新的预后参数和治疗途径的巨大潜力,
CLL细胞与或不与目前的BCR靶向治疗,伊曲替尼。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Asish Kumar Ghosh其他文献
Impact of Annular Solar Eclipse on the Trace Gases and Dynamics of the Lower and Middle Atmosphere: Results Inferred From an Integrated Campaign “Suryagrahan‐2019”
日环食对中低层大气的微量气体和动力学的影响:从综合活动“Suryagrahan-2019”推断的结果
- DOI:
10.1029/2023ea003044 - 发表时间:
2023 - 期刊:
- 影响因子:3.1
- 作者:
S. Das;K. Kishore Kumar;K. Subrahmanyam;M. Venkat Ratnam;K. V. Suneeth;S. Sunilkumar;P. R. Sinha;Asish Kumar Ghosh;Subrata Kumar Das;Sunil Sonwabne;U. MuraliKrishna;Y. Kolte;M. Naja;S. Abhilash;K. Satheesan;V. Rakesh;P. Mahesh;N. Koushik;P. R. Satheesh Chandran;I. Girach;K. V. S. Namboodiri;G. Pandithurai;N. KiranKumar - 通讯作者:
N. KiranKumar
Location-specific weather predictions for Sriharikota (13.72°N, 80.22°E) through numerical atmospheric models during satellite launch campaigns
- DOI:
10.1007/s11069-011-9942-1 - 发表时间:
2011-08-28 - 期刊:
- 影响因子:3.700
- 作者:
D. Bala Subrahamanyam;Radhika Ramachandran;S. Indira Rani;S. Sijikumar;T. J. Anurose;Asish Kumar Ghosh - 通讯作者:
Asish Kumar Ghosh
Asish Kumar Ghosh的其他文献
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{{ truncateString('Asish Kumar Ghosh', 18)}}的其他基金
Study Pro-Oncogenic Role of BCL6 in CLL Tumorigenesis
研究 BCL6 在 CLL 肿瘤发生中的促癌作用
- 批准号:
10512700 - 财政年份:2022
- 资助金额:
$ 16.95万 - 项目类别:
Study Pro-Oncogenic Role of BCL6 in CLL Tumorigenesis
研究 BCL6 在 CLL 肿瘤发生中的促癌作用
- 批准号:
10661814 - 财政年份:2022
- 资助金额:
$ 16.95万 - 项目类别:
Microvesicle Dynamics in B-Cell Chronic Lymphocytic Leukemia Tumor Microenvironme
B 细胞慢性淋巴细胞白血病肿瘤微环境中的微泡动态
- 批准号:
9064090 - 财政年份:2013
- 资助金额:
$ 16.95万 - 项目类别:
Microvesicle Dynamics in B-Cell Chronic Lymphocytic Leukemia Tumor Microenvironme
B 细胞慢性淋巴细胞白血病肿瘤微环境中的微泡动力学
- 批准号:
9295841 - 财政年份:2013
- 资助金额:
$ 16.95万 - 项目类别:
Microvesicle Dynamics in B-Cell Chronic Lymphocytic Leukemia Tumor Microenvironme
B 细胞慢性淋巴细胞白血病肿瘤微环境中的微泡动力学
- 批准号:
8574032 - 财政年份:2013
- 资助金额:
$ 16.95万 - 项目类别:
Microvesicle Dynamics in B-Cell Chronic Lymphocytic Leukemia Tumor Microenvironme
B 细胞慢性淋巴细胞白血病肿瘤微环境中的微泡动力学
- 批准号:
8703043 - 财政年份:2013
- 资助金额:
$ 16.95万 - 项目类别:
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